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MDRTBTx-Monitor

Evaluation of alternative bacteriological measures of response to therapy during the initial 16 weeks of MDR-TB treatment [MDRTBTx-Monitor]

Background

Effective treatment monitoring is vital not only for proper patient management but also for preventing the unnecessary continuation of failing treatment and the emergence of more drug-resistant M. tuberculosis (Mtb). Treatment monitoring by sputum culture is the gold standard for TB, however, this method remains less accessible due to high operational cost, high skills demand, longer turnaround time, and contamination. This study evaluated the effectiveness of alternative methods compared with mycobacterial growth indicator tube, culture time to positivity (MGIT-TTP), and Middle Brook 7H11 Selective (MB7H11S) culture methods for measuring response to therapy during the initial 16 weeks of MDR-TB treatment. The performance of the alternative methods to predict culture conversion at weeks 8, 12, and 16 of treatment were analyzed. The alternative methods include; Concentrated fluorescent smear microscopy (CFM), fluorescein-di-acetate (FDA) AFB vital smear microscopy, and Mtb16sr RNA assays (Molecular Bacterial Load Assay; TBMBLA).

What did we find out?

In a prospective study of 59 patients,  ≥ 18 years of age with MDR/RR-TB and started on MDR-TB treatment short-regimen. Two sputum samples, a spot, and overnight were taken at weeks 0, 2, 4, 6, 8, 12, and 16 of MDR-TB treatment. Samples were pooled and homogenized and divided into three portions; one for; 1) FDA, 2) CFM 3) MGIT. Portion two for TBMBLA and portion three for MB7H11S culture. We compared the percentage positivity of the alternative methods with culture. We also compared the alternative methods for their ability to determine a negative culture patient at weeks 8, 12, and 16.

What did we find out?

Of the 59 participants enrolled, one did not provide sputum samples at baseline. The analysis is based on 58 participants who provided baseline sputum samples. There were more male 37 (63.8) than female participants. The median (interquartile range (IQR) years of the participants were 33 (28.6-37.4). A total of 25 (43.9) participants were HIV-positive, 32 (55.2), previously treated for TB, 35 (61.4) were underweight (BMI <18.5kg/m2) and 20/55 (36.4%) had abnormal chest X-rays. All participants were smear positive on screening, however, the enrollment sample positivity rates at baseline varied according to the test as n (%):  CFM 49/58 (84.5), FDA 40 /58(69.0), TBMBLA, 32/53 (60.4) MGIT 51/52 (98.1) and MB7H11S 47/58 (81.0). During the follow-up, 58 (100%) participants were retained at week 2, 54(93%) at week 4, 52 (89.6%) at week 6, one participant missed week 6 and returned at week 8 raising the retention rate to 91.3%), 52 (89.6%) at week 12 and 50 (86.2%) at week 16.  All alternative methods predicted culture conversion with perfect prediction at weeks 12 and 16 of MDR-TB treatment, but less predictive at week 8. Among HIV positives, using MB7H11S or MGIT as a reference comparator, the prediction for culture conversion varied at week 8 but was 100% for all tests at weeks 12 and 16. None of the baseline patient and bacteriological factors influenced the ability of alternative tests to predict culture conversion at weeks 8, 12, and 16. Our data show that concentrated fluorescent, fluorescein-di-acetate smear microscopy and TBMBLA as suitable alternative measures of response to therapy among MDR-TB patients compared to MB7H11S or MGIT culture. These methods perfectly predict sputum culture conversion at weeks 12 and 16, irrespective of patient clinical characteristics. Despite being more sensitive, MGIT culture is highly prone to contamination, and this increases with the increasing treatment duration.

Impact

Potentially, this study validated alternative methods of monitoring MDR-TB treatment response in resource-limited settings. These will allow quicker decision-making and may help to protect the available treatment regimens and novel TB drugs. If deployed, these methods may improve the efficiency of phase II trials/treatment regimens and lead to reduced delayed results costs in the development of new MDR-TB drugs.